1,3-disubstituted-4-phenyl-1h-pyridin-2-ones

ABSTRACT

The present invention relates to novel compounds, in particular novel pyridinone derivatives according to Formula (I) 
     
       
         
         
             
             
         
       
     
     wherein all radicals are as defined in the application and claims. The compounds according to the invention are positive allosteric modulators of metabotropic receptors—subtype 2 (“mGluR2”) which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.

FIELD OF THE INVENTION

The present invention relates to novel pyridinone-derivatives which arepositive allosteric modulators, of the metabotropic glutamate receptorsubtype 2 (“mGluR2”) and which are useful for the treatment orprevention of neurological and psychiatric disorders associated withglutamate dysfunction and diseases in which the mGluR2 subtype ofmetabotropic receptors is involved. The invention is also directed topharmaceutical compositions comprising such compounds, to processes toprepare such compounds and compositions, and to the use of suchcompounds for the prevention or treatment of neurological andpsychiatric disorders and diseases in which mGluR2 is involved.

BACKGROUND OF THE INVENTION

Glutamate is the major amino acid neurotransmitter in the mammaliancentral nervous system. Glutamate plays a major role in numerousphysiological functions, such as learning and memory but also sensoryperception, development of synaptic plasticity, motor control,respiration, and regulation of cardiovascular function. Furthermore,glutamate is at the centre of several different neurological andpsychiatric diseases, where there is an imbalance in glutamatergicneurotransmission.

Glutamate mediates synaptic neurotransmission through the activation ofionotropic glutamate receptors channels (iGluRs), and the NMDA, AMPA andkainate receptors which are responsible for fast excitatorytransmission.

In addition, glutamate activates metabotropic glutamate receptors(mGluRs) which have a more modulatory role that contributes to thefine-tuning of synaptic efficacy.

Glutamate activates the mGluRs through binding to the largeextracellular amino-terminal domain of the receptor, herein called theorthosteric binding site. This binding induces a conformational changein the receptor which results in the activation of the G-protein andintracellular signaling pathways.

The mGluR2 subtype is negatively coupled to adenylate cyclase viaactivation of Gαi-protein, and its activation leads to inhibition ofglutamate release in the synapse. In the central nervous system (CNS),mGluR2 receptors are abundant mainly throughout cortex, thalamicregions, accessory olfactory bulb, hippocampus, amygdala,caudate-putamen and nucleus accumbens.

Activating mGluR2 was shown in clinical trials to be efficacious totreat anxiety disorders. In addition, activating mGluR2 in variousanimal models was shown to be efficacious, thus representing a potentialnovel therapeutic approach for the treatment of schizophrenia, epilepsy,addiction/drug dependence, Parkinson's disease, pain, sleep disordersand Huntington's disease.

To date, most of the available pharmacological tools targeting mGluRsare orthosteric ligands which activate several members of the family asthey are structural analogs of glutamate.

A new avenue for developing selective compounds acting at mGluRs is toidentify compounds that act through allosteric mechanisms, modulatingthe receptor by binding to a site different from the highly conservedorthosteric binding site.

Positive allosteric modulators of mGluRs have emerged recently as novelpharmacological entities offering this attractive alternative. Variouscompounds have been described as mGluR2 positive allosteric modulators.WO2004/092135 (NPS & Astra Zeneca), WO2004/018386, WO2006/014918 andWO2006/015158 (Merck), WO2001/56990 (Eli Lilly) and WO2006/030032 (Addex& Janssen Pharmaceutica) describe respectively phenyl sulfonamide,acetophenone, indanone, pyridylmethyl sulfonamide and pyridinonederivatives as mGluR2 positive allosteric modulators. None of thespecifically disclosed compounds therein are structurally related to thecompounds of the present invention.

It was demonstrated that such compounds do not activate the receptor bythemselves. Rather, they enable the receptor to produce a maximalresponse to a concentration of glutamate which by itself induces aminimal response. Mutational analysis has demonstrated unequivocallythat the binding of mGluR2 positive allosteric modulators does not occurat the orthosteric site, but instead at an allosteric site situatedwithin the seven transmembrane region of the receptor.

Animal data are suggesting that positive allosteric modulators of mGluR2have effects in anxiety and psychosis models similar to those obtainedwith orthosteric agonists. Allosteric modulators of mGluR2 were shown tobe active in fear-potentiated startle, and in stress-inducedhyperthermia models of anxiety. Furthermore, such compounds were shownto be active in reversal of ketamine- or amphetamine-inducedhyperlocomotion, and in reversal of amphetamine-induced disruption ofprepulse inhibition of the acoustic startle effect models ofschizophrenia (J. Pharmacol. Exp. Ther. 2006, 318, 173-185;Psychopharmacology 2005, 179, 271-283).

Recent animal studies further reveal that the selective positiveallosteric modulator of metabotropic glutamate receptor subtype 2biphenyl-indanone (BINA) blocks a hallucinogenic drug model ofpsychosis, supporting the strategy of targeting mGluR2 receptors fortreating glutamatergic dysfunction in schizophrenia (Mol. Pharmacol.2007, 72, 477-484).

Positive allosteric modulators enable potentiation of the glutamateresponse, but they have also been shown to potentiate the response toorthosteric mGluR2 agonists such as LY379268 or DCG-IV. These dataprovide evidence for yet another novel therapeutic approach to treatabove mentioned neurological and psychiatric diseases involving mGluR2,which would use a combination of a positive allosteric modulator ofmGluR2 together with an orthosteric agonist of mGluR2.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds having metabotropic glutamatereceptor 2 modulator activity, said compounds having the Formula (I)

and the stereochemically isomeric forms thereof, wherein

-   R¹ is C₁₋₆alkyl; or C₁₋₃alkyl substituted with C₃₋₇cycloalkyl,    phenyl, or phenyl substituted with halo, trifluoromethyl or    trifluoromethoxy;-   R² is halo, trifluoromethyl, C₁₋₃alkyl or cyclopropyl;-   R³ is hydrogen, halo or trifluoromethyl;-   R⁴ is hydrogen, C₁₋₃alkyl, C₁₋₃alkyloxy, hydroxyC₁₋₃alkyl or    tetrahydropyran-2-yloxyC₁₋₃alkyl;-   n is 1 or 2;-   X is a covalent bond, O or NR⁵;-   R⁵ is hydrogen, C₁₋₃alkyl or hydroxyC₂₋₃alkyl;-   Y is O or CR⁶(OH);-   R⁶ is hydrogen or C₁₋₃alkyl; or-   R⁴ and R⁶ form a radical —CH₂—CH₂—;    and the pharmaceutically acceptable salts and solvates thereof.

In one embodiment, the invention relates to a compound according toFormula (I) or a stereochemically isomeric form thereof, wherein

-   R¹ is 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl,    (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;-   R² is chloro, bromo, cyclopropyl or trifluoromethyl;-   R³ is hydrogen, chloro or trifluoromethyl;-   R⁴ is hydrogen or hydroxymethyl;-   n is 2;-   X is a covalent bond, O or NR⁵;-   R⁵ is hydrogen;-   Y is O or CR⁶(OH);-   R⁶ is hydrogen or methyl;    or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the invention relates to a compound according toFormula (I) or a stereochemically isomeric form thereof, wherein

-   R¹ is 1-butyl, 3-methyl-1-butyl, (cyclopropyl)methyl or    2-(cyclopropyl)-1-ethyl;-   R² is chloro;-   R³ is hydrogen or chloro;-   R⁴ is hydrogen or hydroxymethyl;-   n is 2;-   X is a covalent bond, O or NR⁵;-   R⁵ is hydrogen;-   Y is O or CR⁶(OH);-   R⁶ is hydrogen or methyl;    or a pharmaceutically acceptable salt or solvate thereof.

The notation C₁₋₃alkyl as a group or part of a group defines asaturated, straight or branched, hydrocarbon radical having from 1 to 3carbon atoms, such as methyl, ethyl, 1-propyl and 1-methylethyl.

The notation C₁₋₆alkyl as a group or part of a group defines asaturated, straight or branched, hydrocarbon radical having from 1 to 6carbon atoms such as methyl, ethyl, 1-propyl, 1-methylethyl, 1-butyl,2-methyl-1-propyl, 3-methyl-1-butyl, 1-pentyl, 1-hexyl and the like. Thenotation —(CH₂)_(n)— is abbreviated C_(n) in the formulae.

The notation C₃₋₇cycloalkyl defines a saturated, cyclic hydrocarbonradical having from 3 to 7 carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The notation halo or halogen as a group or part of a group is genericfor fluoro, chloro, bromo, iodo.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not, are included within the ambit of thepresent invention.

The pharmaceutically acceptable salts are defined to comprise thetherapeutically active non-toxic acid addition salt forms that thecompounds according to Formula (I) are able to form. Said salts can beobtained by treating the base form of the compounds according to Formula(I) with appropriate acids, for example inorganic acids, for examplehydrohalic acid, in particular hydrochloric acid, hydrobromic acid,sulphuric acid, nitric acid and phosphoric acid; organic acids, forexample acetic acid, hydroxyacetic acid, propanoic acid, lactic acid,pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid,fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclamic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.

Conversely said salt forms can be converted into the free base form bytreatment with an appropriate base.

The compounds according to Formula (I) containing acidic protons mayalso be converted into their therapeutically active non-toxic base saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkaline and earth alkaline metal salts, in particular lithium,sodium, potassium, magnesium and calcium salts, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine, hybramine salts, andsalts with amino acids, for example arginine and lysine.

Conversely, said salt forms can be converted into the free acid forms bytreatment with an appropriate acid.

The term solvate comprises the solvent addition forms as well as thesalts thereof, which the compounds of formula (I) are able to form.Examples of such solvent addition forms are e.g. hydrates, alcoholatesand the like.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible isomeric forms that the compounds of Formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. Theinvention also embraces each of the individual isomeric forms of thecompounds of Formula (I) and their salts and solvates, substantiallyfree, i.e. associated with less than 10%, preferably less than 5%, inparticular less than 2% and most preferably less than 1% of the otherisomers. Thus, when a compound of formula (I) is for instance specifiedas (R), this means that the compound is substantially free of the (S)isomer. Stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration.

Following CAS nomenclature conventions, when two stereogenic centers ofknown absolute configuration are present in a compound, an R or Sdescriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) tothe lowest-numbered chiral center, the reference center. Theconfiguration of the second stereogenic center is indicated usingrelative descriptors [R*,R*] or [R*,S*], where R* is always specified asthe reference center and [R*,R*] indicates centers with the samechirality and [R*,S*] indicates centers of unlike chirality. Forexample, if the lowest-numbered chiral center in the compound has an Sconfiguration and the second center is R, the stereo descriptor would bespecified as S—[R*,S*]. If “α” and “β” are used: the position of thehighest priority substituent on the asymmetric carbon atom in the ringsystem having the lowest ring number, is arbitrarily always in the “α”position of the mean plane determined by the ring system. The positionof the highest priority substituent on the other asymmetric carbon atomin the ring system (hydrogen atom in compounds according to Formula (I))relative to the position of the highest priority substituent on thereference atom is denominated “α”, if it is on the same side of the meanplane determined by the ring system, or “β”, if it is on the other sideof the mean plane determined by the ring system.

In the framework of this application, an element, in particular whenmentioned in relation to a compound according to Formula (I), comprisesall isotopes and isotopic mixtures of this element, either naturallyoccurring or synthetically produced, either with natural abundance or inan isotopically enriched form. Radio labelled compounds of Formula (I)may comprise a radioactive isotope selected from the group of ³H, ¹¹C,¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, theradioactive isotope is selected from the group of ³H, ¹¹C and ¹⁸F.

Preparation

The compounds according to the invention can generally be prepared by asuccession of steps, each of which is known to the skilled person. Inparticular, the compounds can be prepared according to the followingsynthesis methods.

The compounds of Formula (I) may be synthesized in the form of racemicmixtures of enantiomers which can be separated from one anotherfollowing art-known resolution procedures. The racemic compounds ofFormula (I) may be converted into the corresponding diastereomeric saltforms by reaction with a suitable chiral acid. Said diastereomeric saltforms are subsequently separated, for example, by selective orfractional crystallization and the enantiomers are liberated therefromby alkali. An alternative manner of separating the enantiomeric forms ofthe compounds of Formula (I) involves liquid chromatography using achiral stationary phase. Said pure stereochemically isomeric forms mayalso be derived from the corresponding pure stereochemically isomericforms of the appropriate starting materials, provided that the reactionoccurs stereospecifically.

A. Preparation of the Final Compounds Experimental Procedure 1

The compounds according to Formula (I) can be prepared by reacting anintermediate of Formula (II) with an intermediate of Formula (III)according to reaction scheme (1), a reaction that is performed in asuitable reaction-inert solvent, such as, for example, 1,4-dioxane ormixtures of inert solvents such as, for example, 1,4-dioxane/DMF, in thepresence of a suitable base, such as, for example, aqueous NaHCO₃ orNa₂CO₃, a Pd-complex catalyst such as, for example,tetrakis(triphenylphosphine)palladium(0), heating for a suitable periodof time that allows the completion of the reaction either undertraditional heating or under microwave irradiation. W is a groupsuitable for Pd mediated coupling with boronic acids or boronic esters,such as, for example, a halogen or triflate and R⁵ and R⁶ may behydrogen or alkyl, or may be taken together to form for example thebivalent radical of formula —CH₂CH₂—, —CH₂CH₂CH₂—, or —C(CH₃)₂C(CH₃)₂—.In reaction scheme (1), all other variables are defined as in Formula(I).

Experimental Procedure 2

Alternatively, compounds according to Formula (I), in the case of R²being halogen, can be prepared by reacting an intermediate of Formula(IV) with a N-halosuccinimide reagent such as, for example,N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide, accordingto reaction scheme (2). This reaction is performed in a suitablereaction-inert and aprotic solvent, such as, for example,dichloromethane or dimethylformamide, stirring the reaction mixture at asuitable temperature and for the required time to achieve completion ofthe reaction. In reaction scheme (2), all other variables are defined asin Formula (I).

Such intermediates (II), (III) and (IV) may be prepared according toreaction schemes (3) to (21) (see below). The transformations ofdifferent functional groups, present in the final compounds or in theintermediates, into other functional groups according to Formula (I) canbe performed by synthesis methods well known by the person skilled inthe art.

B. Preparation of the Intermediate Compounds Experimental Procedure 3

Intermediates of Formula (II-a) can be prepared by reacting anintermediate of Formula (V) with a suitable halogenating agent such as,for example, phosphorus oxybromide, a reaction that is performed in asuitable reaction-inert solvent such as, for example, DMF, at amoderately elevated temperature such as, for example, 110° C. Inreaction scheme (3), all variables are defined as in Formula (I).

Experimental Procedure 4

Intermediates of Formula (II-b) can be prepared by reacting anintermediate of Formula (V) with triflic anhydride (also calledtrifloromethanesulfonic anhydride), a reaction that is performed in asuitable reaction-inert solvent such as, for example, dichloromethane,in the presence of a base such as, for example, pyridine at a lowtemperature such as, for example, −78° C. In reaction scheme (4), allvariables are defined as in Formula (I).

Experimental Procedure 5

Intermediates of Formula (V-a) (wherein R² is halo), can be prepared byreacting an intermediate of Formula (VI) with a N-halosuccinimidereagent, such as N-chlorosuccinimide, N-bromosuccinimide orN-iodosuccinimide, according to reaction scheme (5). This reaction isperformed in a suitable reaction-inert and aprotic solvent, such as, forexample, dichloromethane or 1,2-dichloroethane, stirring the reactionmixture at a suitable temperature, typically at room temperature, forthe required time to achieve completion of the reaction. In reactionscheme (5), variable R¹ is defined as in Formula (I).

Experimental Procedure 6

Intermediates of Formula (V-b) (wherein R²=trifluoromethyl, C₁₋₃alkyl orcyclopropyl), can be prepared by hydrogenation of intermediates ofFormula (VII), in a suitable reaction-inert solvent such as, forexample, ethanol, in the presence of a catalyst such as, for example,10% palladium on activated carbon, for a period of time that ensures thecompletion of the reaction, typically at room temperature and 1atmosphere of hydrogen for 2 hours. In reaction scheme (6), variable R¹is defined as in Formula (I).

Experimental Procedure 7

Intermediates of Formula (VI) can be prepared by hydrogenolysis ofintermediates of Formula (VIII), in a suitable reaction-inert solventsuch as, for example, ethanol, in the presence of a catalyst such as,for example, 10% palladium on activated carbon, for a period of timethat ensures the completion of the reaction, typically at roomtemperature and 1 atmosphere of hydrogen for 2 hours. In reaction scheme(7), variable R′ is defined as in Formula (I).

Experimental Procedure 8

Intermediates of Formula (VIII) can be prepared by art known proceduresby reacting commercially available 4-benzyloxy-1H-pyridin-2-one with acommercially available alkylating agent of Formula (IX), in which Z is asuitable leaving group, using a base such as, for example, K₂CO₃, and,optionally an iodine salt such as, for example, KI, in an inert solventsuch as, for example, acetonitrile or DMF, at a moderately hightemperature such as, for example, 80-120° C., for a suitable period oftime that allows the completion of the reaction, for example 16 hours.In reaction scheme (8), variable R′ is defined as in Formula (I) and Zis a suitable leaving group such as, for example, halogen.

Experimental Procedure 9

Intermediates of Formula (VII-a) can be prepared by reacting anintermediate of Formula (X) with a commercially availableN-halosuccinimide, such as N-chloro- (NCS), N-bromo- (NBS) orN-iodosuccinimide (NIS), in a suitable reaction-inert solvent such as,for example, DMF, dichloromethane or acetic acid, typically at roomtemperature for 1 to 24 hours. In reaction scheme (9), variable R′ isdefined as in Formula (I).

Experimental Procedure 10

Intermediates of Formula (VII-b) can be prepared by reacting anintermediate of Formula (VII-a), wherein Halo is iodine, withcommercially available methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, ina suitable reaction-inert solvent such as, for example, DMF, in presenceof a suitable copper salt such as copper(I) iodide, heating for asuitable period of time that allows the completion of the reaction, forexample at 100° C. for 5 hours. In reaction scheme (10), variable R′ isdefined as in Formula (I).

Experimental Procedure 11

Intermediates of Formula (VII-c) can be prepared by reacting anintermediate of Formula (VII-a) with a C₁₋₃alkyl- or cyclopropyl-boronicacid derivative such as, for example, cyclopropylboronic acid ormethylboronic acid, in a suitable reaction-inert solvent such as, forexample, 1,4-dioxane, in the presence of a suitable palladiumcatalyst-complex such as, for example,[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)—DCMcomplex, and in the presence of a suitable base such as NaHCO₃ heatingfor a suitable period of time that allows the completion of thereaction, for example at 175° C. for 20 minutes under microwaveirradiation. In reaction scheme (11), variable R′ is defined as inFormula (I).

Experimental Procedure 12

Intermediates of Formula (III) can be prepared by art known proceduresby reacting an intermediate of Formula (XI) with a suitable boron sourcesuch as, for example, bis(pinacolato)diboron in the presence of apalladium catalyst such as, for example,1,1″-bis(diphenylphosphino)ferrocenepalladium(II)dichloride in a inertsolvent such as, for example, dichloromethane, in the presence of asuitable salt such as, for example, potassium acetate at moderately hightemperature such as, for example, 110° C. for as for example 16 hours.

Additionally, intermediates of Formula (III) can be prepared by artknown procedures of metal-halogen exchange and subsequent reaction withan appropriate boron source from intermediates of Formula (XI). Thus,for example reaction of an intermediate of Formula (XI) with an organolithium compound such as, for example, n-butyllithium at a moderatelylow temperature such as, for example, −40° C. in an inert solvent suchas, for example, THF followed by subsequent reaction with an appropriateboron source such as, for example, trimethoxyborane. In reaction scheme(12), all variables are defined as in Formula (I) and R⁵ and R⁶ may behydrogen or alkyl, or may be taken together to form for example thebivalent radical of formula —CH₂CH₂—, —CH₂CH₂CH₂—, or —C(CH₃)₂C(CH₃)₂—.

Experimental Procedure 13

Additionally, intermedates of Formula (III-a) can be prepared byreacting the commercially available intermediate of Formula (XII) with acyclic ketone derivative of Formula (XIII) under reductive aminationconditions that are known by those skilled in the art, such as forexample, in the presence of triacetoxy borohydride in a suitablereaction-inert solvent, such as for example 1,2-dichloroethane, at asuitable temperature, typically room temperature, for a suitable periodof time that allows the completion of the reaction.

Experimental Procedure 14

Intermediates according to Formula (IV) can be prepared by reacting anintermediate of Formula (II-a), in which R²═H, with an intermediate ofFormula (III) according to reaction scheme (14). This reaction may beperformed in a suitable reaction-inert solvent such as, for example,1,4-dioxane or mixtures of inert solvents such as, for example,1,4-dioxane/DMF. The reaction may be performed in the presence of asuitable base such as, for example, aqueous NaHCO₃ or Na₂CO₃, aPd-complex catalyst such as, for example,tetrakis(triphenylphosphine)palladium(0), heating for a suitable periodof time that allows the completion of the reaction either undertraditional heating or under microwave irradiation. In reaction scheme(14), all variables are defined as in Formula (I). W is a group suitablefor Pd mediated coupling with boronic acids or boronic esters, such as,for example, a halogen or triflate and R⁵ and R⁶ may be hydrogen oralkyl or may be taken together to form for example the bivalent radicalof formula —CH₂CH₂—, —CH₂CH₂CH₂—, or —C(CH₃)₂C(CH₃)₂—.

Experimental Procedure 15

Intermediates of Formula (XI-a) can be prepared by art known proceduresby reacting an aniline intermediate of Formula (XIV-a) with a cyclicketone derivative of Formula (XIII), under reductive aminationconditions that are known by those skilled in the art, such as forexample, in the presence of triacetoxy borohydride in a suitablereaction-inert solvent, such as for example 1,2-dichloroethane, at asuitable temperature, typically room temperature, for a suitable periodof time that allows the completion of the reaction. In reaction scheme(15), all variables are defined as in Formula (I) and halo- may bechloro-, bromo- or iodo-.

Experimental Procedure 16

Intermediates of Formula (XI-b) can be prepared by art known proceduresby reacting a a phenol intermediate of Formula (XIV-b) with a cyclicalcohol of Formula (XV), in the presence of a phosphine, such as forexample triphenylphosphine and a suitable coupling agent forMitsunobu-like couplings, such as for example di-tert-butylazadicarboxylate in a inert solvent such as, for example,dichloromethane, at moderately low temperature such as, for example, 25°C. for as for example 2 hours. In reaction scheme (16), all variablesare defined as in Formula (I) and halo- may be chloro-, bromo- or iodo-.

Experimental Procedure 17

Additionally, intermediates of Formula (XI-c) can be prepared by artknown procedures of metal-halogen exchange from intermediates of Formula(XIV-c) and subsequent reaction with a cyclic ketone of Formula (XIII).Thus for example reaction of an intermediate of Formula (XI-c) with anorgano lithium compound such as, for example, n-butyllithium at amoderately low temperature such as, for example, −40° C. in an inertsolvent such as, for example, THF followed by subsequent reaction withtetrahydro-4H-pyran-4-one. In reaction scheme (17), all variables aredefined as in Formula (I) and halo- may be chloro-, bromo- or iodo-.

Experimental Procedure 18

Additionally, intermediates of Formula (XI-d) can be prepared by artknown procedures in a two step sequence consisting in a dehydratationreaction followed by hydrogenation reaction from intermediates ofFormula (XI-c). Thus for example reaction of an intermediate of Formula(XI-c) with an acid such as, for example, p-toluenesulfonic acidmonohydrate at a moderately high temperature such as, for example, 100°C. in an inert solvent such as, for example, toluene for as for example2 h, yields an intermediate of Formula (XI-e). Then, this intermediatecan be hydrogenated in the presence of a catalytic amount of suitablecatalyst such as for example platinum oxide in an solvent such as forexample ethanol to yield intermediate (XI-d). In reaction scheme (18)halo- may be chloro-, bromo- or iodo-. All other variables are definedas in Formula (I).

Experimental Procedure 19

Additionally, intermediates of Formula (XI-0 can be prepared by artknown procedures from commercially available or synthetically accessible(4-halophenyl)-acetic acid alkylester derivatives, in a two stepsequence consisting in an alkylation reaction with an appropriatedi-halo-derivative followed by reduction of the ester functional groupto alcohol. Thus for example reaction with 2-chloroethyl ether inpresence of a base, such as sodium hydride, in an inert solvent such asDMF, at the appropriate temperature and for the period of time requiredto ensure the completion of the reaction, typically at room temperaturefor 10-16 hours, yields an intermediate of formula (XI-g). Then, thisintermediate can be reacted with a metal reducing reagent, such as forexample lithium aluminium hydride, in an inert solvent such astetrahydrofuran, at the appropriate temperature and for the period oftime required to ensure the completion of the reaction, typically −10°C. to room temperature for 2 hours, to yield an intermediate of Formula(XI-f). In reaction scheme (19), all variables are defined as in Formula(I) and halo- may be chloro-, bromo- or iodo-.

Experimental Procedure 20

Additionally, intermediates of Formula (XI) can be prepared by art knownprocedures from aniline-like intermediates of Formula (XVI) via aSandmeyer type reaction. In reaction scheme (20), all variables aredefined as in Formula (I) and halo- may be chloro-, bromo- or iodo-.

Experimental Procedure 21

Intermediates of Formula (XVI) can be prepared by art known proceduresfrom intermediates of Formula (XVII) via reduction of the nitro group tothe amino function by art known procedures such as catalytichydrogenation or the use of tin(II) chloride dihydrate as a reductingagent. In reaction scheme (21), all variables are defined as in Formula(I).

Experimental Procedure 22

Intermediates of Formula (XVII) can be prepared by art known proceduresby reacting an intermediate of Formula (XVIII) with a suitableintermediate of Formula (XIX), in the presence of a suitable base suchas, for example, cesium carbonate in an inert solvent such as, forexample, dimethylformamide or acetonitrile, at a convenient temperatureand for a suitable period of time to ensure completion of the reaction.In reaction scheme (22) all variables are defined as in Formula (I).

The starting materials according to Formulas (IX), (XIII), (XIV-a, -band -c), (XV), (XVIII) and (XIX) are intermediates that are eithercommercially available or may be prepared according to conventionalreaction procedures generally known by those skilled in the art.

Pharmacology

The compounds provided in this invention are positive allostericmodulators of metabotropic glutamate receptors, in particular they arepositive allosteric modulators of mGluR2. The compounds of the presentinvention do not appear to bind to the glutamate recognition site, theorthosteric ligand site, but instead to an allosteric site within theseven transmembrane region of the receptor. In the presence of glutamateor an agonist of mGluR2, the compounds of this invention increase themGluR2 response. The compounds provided in this invention are expectedto have their effect at mGluR2 by virtue of their ability to increasethe response of such receptors to glutamate or mGluR2 agonists,enhancing the response of the receptor. Hence, the present inventionrelates to a compound according to the present invention for use as amedicine, as well as to the use of a compound according to the inventionor a pharmaceutical composition according to the invention for themanufacture of a medicament for treating or preventing, in particulartreating, a condition in a mammal, including a human, the treatment orprevention of which is affected or facilitated by the neuromodulatoryeffect of allosteric modulators of mGluR2, in particular positiveallosteric modulators thereof. The present invention also relates to acompound according to the present invention or a pharmaceuticalcomposition according to the invention for use in the manufacture of amedicament for treating or preventing, in particular treating, acondition in a mammal, including a human, the treatment or prevention ofwhich is affected or facilitated by the neuromodulatory effect ofallosteric modulators of mGluR2, in particular positive allostericmodulators thereof. The present invention also relates to a compoundaccording to the present invention or a pharmaceutical compositionaccording to the invention for treating or preventing, in particulartreating, a condition in a mammal, including a human, the treatment orprevention of which is affected or facilitated by the neuromodulatoryeffect of allosteric modulators of mGluR2, in particular positiveallosteric modulators thereof.

Also, the present invention relates to the use of a compound accordingto the invention or a pharmaceutical composition according to theinvention for the manufacture of a medicament for treating, preventing,ameliorating, controlling or reducing the risk of various neurologicaland psychiatric disorders associated with glutamate dysfunction in amammal, including a human, the treatment or prevention of which isaffected or facilitated by the neuromodulatory effect of positiveallosteric modulators of mGluR2.

Where the invention is said to relate to the use of a compound orcomposition according to the invention for the manufacture of amedicament for e.g. the treatment of a mammal, it is understood thatsuch use is to be interpreted in certain jurisdictions as a method ofe.g. treatment of a mammal, comprising administering to a mammal in needof such e.g. treatment, an effective amount of a compound or compositionaccording to the invention.

In particular, the neurological and psychiatric disorders associatedwith glutamate dysfunction, include one or more of the followingconditions or diseases: acute neurological and psychiatric disorderssuch as, for example, cerebral deficits subsequent to cardiac bypasssurgery and grafting, stroke, cerebral ischemia, spinal cord trauma,head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronaldamage, dementia (including AIDS-induced dementia), Alzheimer's disease,Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage,retinopathy, cognitive disorders, idiopathic and drug-inducedParkinson's disease, muscular spasms and disorders associated withmuscular spasticity including tremors, epilepsy, convulsions, migraine(including migraine headache), urinary incontinence, substancetolerance, substance withdrawal (including substances such as, forexample, opiates, nicotine, tobacco products, alcohol, benzodiazepines,cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety(including generalized anxiety disorder, panic disorder, and obsessivecompulsive disorder), mood disorders (including depression, mania,bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus,macular degeneration of the eye, emesis, brain edema, pain (includingacute and chronic states, severe pain, intractable pain, neuropathicpain, and post-traumatic pain), tardive dyskinesia, sleep disorders(including narcolepsy), attention deficit/hyperactivity disorder, andconduct disorder.

In particular, the condition or disease is a central nervous systemdisorder selected from the group of anxiety disorders, psychoticdisorders, personality disorders, substance-related disorders, eatingdisorders, mood disorders, migraine, epilepsy or convulsive disorders,childhood disorders, cognitive disorders, neurodegeneration,neurotoxicity and ischemia.

Preferably, the central nervous system disorder is an anxiety disorder,selected from the group of agoraphobia, generalized anxiety disorder(GAD), obsessive-compulsive disorder (OCD), panic disorder,posttraumatic stress disorder (PTSD), social phobia and other phobias.

Preferably, the central nervous system disorder is a psychotic disorderselected from the group of schizophrenia, delusional disorder,schizoaffective disorder, schizophreniform disorder andsubstance-induced psychotic disorder

Preferably, the central nervous system disorder is a personalitydisorder selected from the group of obsessive-compulsive personalitydisorder and schizoid, schizotypal disorder.

Preferably, the central nervous system disorder is a substance-relateddisorder selected from the group of alcohol abuse, alcohol dependence,alcohol withdrawal, alcohol withdrawal delirium, alcohol-inducedpsychotic disorder, amphetamine dependence, amphetamine withdrawal,cocaine dependence, cocaine withdrawal, nicotine dependence, nicotinewithdrawal, opioid dependence and opioid withdrawal.

Preferably, the central nervous system disorder is an eating disorderselected from the group of anorexia nervosa and bulimia nervosa.

Preferably, the central nervous system disorder is a mood disorderselected from the group of bipolar disorders (I & II), cyclothymicdisorder, depression, dysthymic disorder, major depressive disorder andsubstance-induced mood disorder.

Preferably, the central nervous system disorder is migraine.

Preferably, the central nervous system disorder is epilepsy or aconvulsive disorder selected from the group of generalized nonconvulsiveepilepsy, generalized convulsive epilepsy, petit mal status epilepticus,grand mal status epilepticus, partial epilepsy with or withoutimpairment of consciousness, infantile spasms, epilepsy partialiscontinua, and other forms of epilepsy.

Preferably, the central nervous system disorder isattention-deficit/hyperactivity disorder.

Preferably, the central nervous system disorder is a cognitive disorderselected from the group of delirium, substance-induced persistingdelirium, dementia, dementia due to HIV disease, dementia due toHuntington's disease, dementia due to Parkinson's disease, dementia ofthe Alzheimer's type, substance-induced persisting dementia and mildcognitive impairment.

Of the disorders mentioned above, the treatment of anxiety,schizophrenia, migraine, depression, and epilepsy are of particularimportance.

At present, the fourth edition of the Diagnostic & Statistical Manual ofMental Disorders (DSM-IV) of the American Psychiatric Associationprovides a diagnostic tool for the identification of the disordersdescribed herein. The person skilled in the art will recognize thatalternative nomenclatures, nosologies, and classification systems forneurological and psychiatric disorders described herein exist, and thatthese evolve with medical and scientific progresses.

Because such positive allosteric modulators of mGluR2, includingcompounds of Formula (I), enhance the response of mGluR2 to glutamate,it is an advantage that the present methods utilize endogenousglutamate.

Because positive allosteric modulators of mGluR2, including compounds ofFormula (I), enhance the response of mGluR2 to agonists, it isunderstood that the present invention extends to the treatment ofneurological and psychiatric disorders associated with glutamatedysfunction by administering an effective amount of a positiveallosteric modulator of mGluR2, including compounds of Formula (I), incombination with an mGluR2 agonist.

The compounds of the present invention may be utilized in combinationwith one or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula (I) or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone.

Pharmaceutical Compositions

The invention also relates to a pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and, as activeingredient, a therapeutically effective amount of a compound accordingto the invention, in particular a compound according to Formula (I), apharmaceutically acceptable salt thereof, a solvate thereof or astereochemically isomeric form thereof.

The compounds according to the invention, in particular the compoundsaccording to Formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms thereof, or anysubgroup or combination thereof may be formulated into variouspharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs.

To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, optionally in salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier or diluent, which carrier or diluentmay take a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirable in unitary dosage form suitable, in particular, foradministration orally, rectally, percutaneously, by parenteral injectionor by inhalation. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as, for example, suspensions, syrups,elixirs, emulsions and solutions; or solid carriers such as, forexample, starches, sugars, kaolin, diluents, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of the ease in administration, oraladministration is preferred, and tablets and capsules represent the mostadvantageous oral dosage unit forms in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. Also included are solid form preparations that areintended to be converted, shortly before use, to liquid formpreparations. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical compositionwill comprise from 0.05 to 99% by weight, preferably from 0.1 to 70% byweight, more preferably from 0.1 to 50% by weight of the activeingredient, and, from 1 to 99.95% by weight, preferably from 30 to 99.9%by weight, more preferably from 50 to 99.9% by weight of apharmaceutically acceptable carrier, all percentages being based on thetotal weight of the composition.

As already mentioned, the invention also relates to a pharmaceuticalcomposition comprising the compounds according to the invention and oneor more other drugs in the treatment, prevention, control, amelioration,or reduction of risk of diseases or conditions for which compounds ofFormula (I) or the other drugs may have utility as well as to the use ofsuch a composition for the manufacture of a medicament. The presentinvention also relates to a combination of a compound according to thepresent invention and a mGluR2 orthosteric agonist. The presentinvention also relates to such a combination for use as a medicine. Thepresent invention also relates to a product comprising (a) a compoundaccording to the present invention, a pharmaceutically acceptable saltthereof or a solvate thereof, and (b) a mGluR2 orthosteric agonist, as acombined preparation for simultaneous, separate or sequential use in thetreatment or prevention of a condition in a mammal, including a human,the treatment or prevention of which is affected or facilitated by theneuromodulatory effect of mGluR2 allosteric modulators, in particularpositive mGluR2 allosteric modulators. The different drugs of such acombination or product may be combined in a single preparation togetherwith pharmaceutically acceptable carriers or diluents, or they may eachbe present in a separate preparation together with pharmaceuticallyacceptable carriers or diluents.

The following examples are intended to illustrate but not to limit thescope of the present invention.

Chemistry

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Unless otherwise noted, allstarting materials were obtained from commercial suppliers and usedwithout further purification.

Hereinafter, “THF” means tetrahydrofuran; “DMF” meansN,N-dimethylformamide; “EtOAc” means ethyl acetate; “DCM” meansdichloromethane; “DME” means 1,2-dimethoxyethane; “DCE” means1,2-dichloroethane; “DIPE” means diisopropylether; “DMSO” meansdimethylsulfoxide; “DBU” means 1,8-diaza-7-bicyclo[5.4.0]undecene;

Microwave assisted reactions were performed in a single-mode reactor:Initiator™ Sixty EXP microwave reactor (Biotage AB), or in a multimodereactor: MicroSYNTH Labstation (Milestone, Inc.).

Description 1 4-Benzyloxy-1-butyl-1H-pyridin-2-one (D1)

To a solution of 4-benzyloxy-JH-pyridin-2-one (5.0 g, 24.84 mmol) inacetonitrile (200 ml) were added 1-bromobutane (3.75 g, 27.33 mmol) andpotassium carbonate (10.3 g, 74.52 mmol) and the mixture was heated atreflux for 16 hours. The reaction mixture was filtered throughdiatomaceous earth and concentrated in vacuo. The crude residue was thentriturated with diethylether to yield pure D1 (6.26 g, 98%) as a whitesolid.

Description 2 1-Butyl-4-hydroxy-1H-pyridin-2-one (D2)

A mixture of intermediate D1 (2.01 g, 7.83 mmol) and a catalytic amountof 10% palladium on activated carbon in ethanol (300 ml) was stirredunder a hydrogen atmosphere for two hours. The mixture was filteredthrough diatomaceous earth and the solvent was evaporated in vacuo toyield intermediate D2 (1.3 g, 100%) that was used without furtherpurification.

Description 3 4-Bromo-1-butyl-1H-pyridin-2-one (D3)

To a solution of intermediate D2 (1.44 g, 8.6 mmol) in DMF (140 ml) wasadded phosphorus oxybromide (5.4 g, 18.9 mmol) and the mixture washeated at 110° C. for 1 hour. After cooling in an ice bath the solutionwas partitioned between water and EtOAc. After three extractions withEtOAc the combined organic fractions were dried (Na₂SO₄) and the solventevaporated in vacuo. The crude product was purified by columnchromatography (silica gel; DCM as eluent). The desired fractions werecollected and evaporated in vacuo to yield intermediate D3 (1.82 g,93%).

Description 4 4-Bromo-1-(3-methylbutyl)-1H-pyridin-2-one (D4)

Intermediate D4 was prepared following the same procedure implementedfor the synthesis of D3, using4-hydroxy-1-(3-methylbutyl)-1H-pyridin-2-one as starting material, whichwas prepared by the same method used for the synthesis of intermediateD2, by reaction of 4-benzyloxy-1H-pyridin-2-one with1-bromo-3-methylbutane.

Description 5 1-Butyl-3-chloro-4-hydroxy-M-pyridin-2-one (D5)

To a solution of intermediate D2 (2.0 g, 11.96 mmol) in DMF (30 ml) wasadded N-chlorosuccinimide (1.6 g, 11.96 mmol). The reaction was stirredat room temperature overnight and then it was concentrated in vacuo. Thecrude product was purified by column chromatography (silica gel; 0-5%methanol/DCM as eluent) to yield intermediate 05 (2.0 g, 83%).

Description 6 Trifluoro-methanesulfonic acid1-butyl-3-chloro-2-oxo-1,2-dihydropyridin-4-yl ester (D6)

To a solution of intermediate D5 (2.0 g, 9.92 mmol) in DCM (80 ml)cooled at −78° C. was added pyridine (1.60 ml, 19.8 mmol). The resultingsolution was stirred for 10 minutes after which trifloromethanesulfonicanhydride (1.90 ml, 10.9 mmol) was added, and the resulting solution wasstirred at −78° C. for 3 hours. Then the mixture was warmed to roomtemperature and it was quenched by the addition of aqueous saturatedammonium chloride, it was diluted with water and extracted with DCM,dried (Na₂SO₄) and the solvent evaporated in vacuo, yieldingintermediate D6 (3.31 g, 100%) as a crude that was used without furtherpurification.

Description 7(Tetrahydropyran-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amine(D7)

A mixture of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (0.5 g,2.28 mmol), tetrahydropyran-4-one (0.25 ml, 2.73 mmol) and sodiumtriacetoxy-borohydride (0.71 g, 3.42 mmol) in DCE (50 ml) was stirred atroom temperature for 16 hours. The crude was filtered over diatomaceousearth, washed with DCM and the filtrate was evaporated in vacuo to yieldD7 (0.69 g) that was used without further purification.

Description 81-(3-Methylbutyl)-4-[4-(tetrahydropyran-4-ylamino)-phenyl]-1H-pyridin-2-one(D8)

A suspension of intermediate D4 (0.46 g, 1.9 mmol), intermediate D7(0.69 g, 2.28 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.21g, 0.19 mmol) in a mixture of dioxane (4 ml) and saturated aqueoussodium carbonate (4 ml) was heated at 150° C. for 10 minutes, undermicrowave irradiation. The crude was filtered over diatomaceous earthand washed with EtOAc. The organic layer was separated and washed withbrine, dried (Na₂SO₄) and the solvent evaporated in vacuo. The crudeproduct was purified by column chromatography (silica gel; DCM/EtOAc 8:2and finally EtOAc as eluent). The desired fractions were collected andevaporated in vacuo to yield D8 (0.64 g, 95%) as a yellow solid.

Description 9 4-(4-Bromo-phenyl)-tetrahydropyran-4-carboxylic acidmethyl ester (D9)

To a stirred solution of (4-bromophenyl)-acetic acid methylester (12.52g, 54.6 mmol) and 15-crown-5 (1.2 g, 5.46 mmol) in DMF (100 ml) at roomtemperature was added NaH (60%) (4.74 g, 119 mmol) portionwise. Afterstirring at room temperature for 40 minutes, NaI (8.14 g, 54.6 mmol) and2-chloroethyl ether (13.76 g, 96.2 mmol) were added. The reactionmixture was stirred at room temperature for 10 hours, after which thesolvent was evaporated in vacuo. The residue was treated with a mixtureof EtOAc and toluene (1:1) and washed with a solution of 0.5 N HCl. Theaqueous layer was further extracted with more EtOAc/toluene (1:1) andthe combined organic extracts were washed with water, then with anaqueous saturated solution of NaHCO₃ and finally with brine. Thecombined organic extracts were dried (Na₂SO₄) and the solvent evaporatedin vacuo. The crude residue was triturated with n-heptane and thesoluble fraction was evaporated to dryness under reduced pressure toyield D9 (3.96 g, 24%) as a yellow liquid.

Description 10 [4-(4-Bromophenyl)-tetrahydropyran-4-yl]-methanol (D10)

To a solution of intermediate D9 (1.07 g, 3.58 mmol) in THF (20 ml)stirred at −10° C. under N₂ atmosphere, was added a 1.0 M solution oflithium aluminum hydride in THF dropwise (3.58 ml, 3.58 mmol). Theresulting solution was gradually warmed to room temperature and furtherstirred for 2 hours. After cooling to 0° C. an aqueous 10% NaOH solutionwas carefully added and the resulting mixture was allowed to reach roomtemperature. Then it was extracted with DCM, dried (Na₂SO₄) and thesolvent evaporated in vacuo to yield intermediate D10 (0.96 g, 99%) as awhite solid that was used without further purification.

Description 11{4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-tetrahydropyran-4-yl}-methanol(D11)

To a solution of intermediate D10 (0.96 g, 3.53 mmol) in dioxane (12 ml)and DMF (3 ml) were added bis(pinacolato)diboron (1.43 g, 5.65 mmol) andpotassium acetate (1.04 g, 10.59 mmol). The mixture was degassed andthen [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)—complex with DCM (1:1) (0.09 g, 0.106 mmol) was added. The reactionmixture was heated at 150° C. for 40 minutes under microwaveirradiation. After cooling to room temperature water was added and themixture was extracted with EtOAc. The organic fraction was dried(Na₂SO₄) and the solvent evaporated in vacuo. The crude residue waspurified by column chromatography (silica gel; DCM as eluent). Thedesired fractions were collected and evaporated in vacuo to afford anoily residue that was triturated with n-heptane to yield D11 (0.65 g,58%) as a white solid.

Description 124-(Tetrahydropyran-2-yloxymethyl)-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-tetrahydropyran(D12)

A mixture of intermediate D11 (0.58 g, 1.8 mmol), 3,4-dihydro-2H-pyran(0.2 ml, 2.18 mmol) and p-toluenesulfonic acid (catalytic amount) in dryDCM (20 ml) was stirred at room temperature for 1 hour. The reactionmixture was then washed with an aqueous saturated solution of NaHCO₃,the combined organic extracts were dried (Na₂SO₄) and the solvent wasevaporated in vacuo. The crude residue was purified by columnchromatography (silica gel; DCM as eluent). The desired fractions werecollected and evaporated in vacuo to yield D12 (0.73 g, 100%) that wasused without further purification.

Example 13-Chloro-1-(3-methylbutyl)-4-[4-(tetrahydropyran-4-ylamino)-phenyl]-1H-pyridin-2-one(E1)

A solution of intermediate D8 (0.65 g, 1.91 mmol) andN-chlorosuccinimide (0.25 g, 1.91 mmol) in DMF (10 ml) was stirred at45° C. for 16 hours. After cooling to room temperature water was addedand the solution was extracted with EtOAc, The organic layer wasseparated and washed with brine, dried (Na₂SO₄) and the solventevaporated in vacuo. The crude product was purified by columnchromatography (silica gel; DCM/EtOAc 8:2 as eluent). The desiredfractions were collected and evaporated in vacuo to yield E1 (0.20 g,28%) as a pale pink solid.

Melting point: >300° C.

Example 21-Butyl-3-chloro-4-{4-[4-(tetrahydropyran-2-yloxymethyl)-tetrahydropyran-4-yl]-phenyl}-1H-pyridin-2-one(E2)

A mixture of intermediate D6 (0.17 g, 0.5 mmol), intermediate D12 (0.2g, 0.5 mmol), catalyst tetrakis(triphenylphosphine)palladium(0) (0.03 g,0.025 mmol) and NaHCO₃ (3 g, excess) in dioxane (6 ml) was heated at150° C. for 10 minutes under microwave irradiation. After cooling toroom temperature the reaction mixture was filtered through diatomaceousearth, treated with EtOAc and the organic layer was washed with waterand then with brine. The organic fraction was dried (Na₂SO₄) and thesolvent evaporated in vacuo. The crude residue was purified by columnchromatography (silica gel; 0-10% EtOAc/DCM as eluent). The desiredfractions were collected and evaporated in vacuo to yield E2 (0.10 g,45%) as a colorless oil.

Example 31-Butyl-3-chloro-4-[4-(4-hydroxymethyl-tetrahydropyran-4-yl)-phenyl]-1H-pyridin-2-one(E3)

A mixture of compound E2 (0.10 g, 0.22 mmol) and a catalytic amount ofp-toluenesulfonic acid in methanol (10 ml) was stirred at roomtemperature for 1 hour. The solvent was evaporated in vacuo and theresulting residue was taken up with DCM, washed with an aqueoussaturated solution of NaHCO₃, the combined organic extracts were dried(Na₂SO₄) and the solvent was evaporated in vacuo. The crude residue waspurified by column chromatography (silica gel; 0-30% EtOAc/DCM aseluent). The desired fractions were collected and evaporated in vacuo toyield E3 (0.05 g, 61%) as a colourless oil.

Compounds E4 to E9 (Table 1) were prepared in a similar manner.

Physico-Chemical Data LCMS—General Procedure

The HPLC measurement was performed using a HP 1100 from AgilentTechnologies comprising a pump (quaternary or binary) with degasser, anautosampler, a column oven, a diode-array detector (DAD) and a column asspecified in the respective methods below. Flow from the column wassplit to a MS spectrometer. The MS detector was configured with anelectrospray ionization source. Nitrogen was used as the nebulizer gas.The source temperature was maintained at 140° C. Data acquisition wasperformed with MassLynx-Openlynx software.

In addition to the general procedure: Reversed phase HPLC was carriedout on an XDB-C18 cartridge (1.8 μm, 2.1×30 mm) from Agilent, with aflow rate of 1 ml/min, at 60° C. The gradient conditions used are: 90% A(0.5 g/l ammonium acetate solution), 5% B (acetonitrile), 5% C(methanol) to 50% B and 50% C in 6.5 minutes, to 100% B at 7 minutes andequilibrated to initial conditions at 7.5 minutes until 9.0 minutes.Injection volume 2 μl. High-resolution mass spectra (Time of Flight,TOF) were acquired only in positive ionization mode by scanning from 100to 750 in 0.5 seconds using a dwell time of 0.1 seconds. The capillaryneedle voltage was 2.5 kV and the cone voltage was 20 V.Leucine-Enkephaline was the standard substance used for the lock masscalibration.

Melting Points

For a number of compounds, melting points were determined in opencapillary tubes on a Mettler FP62 apparatus. Melting points weremeasured with a temperature gradient of 3 or 10° C./minute. Maximumtemperature was 300° C. The melting point was read from a digitaldisplay and were obtained with experimental uncertainties that arecommonly associated with this analytical method.

Table 1 lists compounds of Formula (I) that were prepared according toone of the above Examples (Ex. no.).

TABLE 1

Melting Point M. Wt RT Ex. R1 R3 R4 X Y (° C.) Free base MH+ (min) E1

H H NH O decomposes 374 375 4.28 E2

H

bond O n.d. n.d. n.d. n.d. E3

H —CH₂OH bond O n.d. 375 376 3.34 E4

3′-Cl H O O 154 407 408 4.59 E5

3′-CF₃ H NH O 173 426 427 4.49 E6

3′-Cl H NH O 231 392 393 4.15 E7

3′-Cl H NH C(CH₃)OH 227.4 422 423 4.73 E8

H H NH CHOH (cis) 186.2 374 375 3.95 E9

H H NH CHOH (trans) 263.5 374 375 3.62 n.d.: not determined

D. Pharmacological Examples

The compounds provided in the present invention are positive allostericmodulators of mGluR2. These compounds appear to potentiate' glutamateresponses by binding to an allosteric site other than the glutamatebinding site. The response of mGluR2 to a concentration of glutamate isincreased when compounds of Formula (I) are present. Compounds ofFormula (I) are expected to have their effect substantially at mGluR2 byvirtue of their ability to enhance the function of the receptor. Thebehaviour of positive allosteric modulators tested at mGluR2 using the[³⁵S]GTPγS binding assay method described below and which is suitablefor the identification of such compounds, and more particularly thecompounds according to Formula (I), are shown in Table 4.

[³⁵S]GTPγS Binding Assay

The [³⁵S]GTPγS binding assay is a functional membrane-based assay usedto study G-protein coupled receptor (GPCR) function wherebyincorporation of a non-hydrolysable form of GTP, [³⁵S]GTPγS (guanosine5′-triphosphate, labelled with gamma-emitting ³⁵S), is measured. TheG-protein α subunit catalyzes the exchange of guanosine 5′-diphosphate(GDP) by guanosine triphosphate (GTP) and on activation of the GPCR byan agonist, [³⁵S]GTPγS, becomes incorporated and cannot be cleaved tocontinue the exchange cycle (Harper (1998) Current Protocols inPharmacology 2.6.1-10, John Wiley & Sons, Inc.). The amount ofradioactive [³⁵S]GTPγS incorporation is a direct measure of the activityof the G-protein and hence the activity of the agonist can bedetermined. mGluR2 receptors are shown to be preferentially coupled toGαi-protein, a preferential coupling for this method, and hence it iswidely used to study receptor activation of mGluR2 receptors both inrecombinant cell lines and in tissues (Schaffhauser et al 2003,Pinkerton et al, 2004, Mutel et al (1998) Journal of Neurochemistry.71:2558-64; Schaffhauser et al (1998) Molecular Pharmacology 53:228-33).Here we describe the use of the [³⁵S]GTPγS binding assay using membranesfrom cells transfected with the human mGluR2 receptor and adapted fromSchaffhauser et al ((2003) Molecular Pharmacology 4:798-810) for thedetection of the positive allosteric modulation (PAM) properties of thecompounds of this invention.

Membrane Preparation

CHO-cells were cultured to pre-confluence and stimulated with 5 mMbutyrate for 24 hours, prior to washing in PBS, and then collection byscraping in homogenisation buffer (50 mM Tris-HCl buffer, pH 7.4, 4°C.). Cell lysates were homogenized briefly (15 s) using an ultra-turraxhomogenizer. The homogenate was centrifuged at 23 500×g for 10 minutesand the supernatant discarded. The pellet was resuspended in 5 mMTris-HCl, pH 7.4 and centrifuged again (30 000×g, 20 min, 4° C.). Thefinal pellet was resuspended in 50 mM HEPES, pH 7.4 and stored at −80°C. in appropriate aliquots before use. Protein concentration wasdetermined by the Bradford method (Bio-Rad, USA) with bovine serumalbumin as standard.

[³⁵S]GTPγS Binding Assay

Measurement of mGluR2 positive allosteric modulatory activity of testcompounds in membranes containing human mGluR2 was performed usingfrozen membranes that were thawed and briefly homogenised prior topre-incubation in 96-well microplates (15 μg/assay well, 30 minutes, 30°C.) in assay buffer (50 mM HEPES pH 7.4, 100 mM NaCl, 3 mM MgCl₂, 50 μMGDP, 10 μg/ml saponin,) with increasing concentrations of positiveallosteric modulator (from 0.3 nM to 50 μM) and either a minimalpre-determined concentration of glutamate (PAM assay), or no addedglutamate. For the PAM assay, membranes were pre-incubated withglutamate at EC₂₅ concentration, i.e. a concentration that gives 25% ofthe maximal response glutamate, and is in accordance to published data(Pin et al. (1999) Eur. J. Pharmacol. 375:277-294). After addition of[³⁵S]GTPγS (0.1 nM, f.c.) to achieve a total reaction volume of 200microplates were shaken briefly and further incubated to allow[³⁵S]GTPγS incorporation on activation (30 minutes, 30° C.). Thereaction was stopped by rapid vacuum filtration over glass-fibre filterplates (Unifilter 96-well GF/B filter plates, Perkin-Elmer, DownersGrove, USA) microplate using a 96-well plate cell harvester (Filtermate,Perkin-Elmer, USA), and then by washing three times with 300 μl ofice-cold wash buffer (Na₂PO₄.2H₂0 10 mM, NaH₂PO₄.H₂0 10 mM, pH=7.4).Filters were then air-dried, and 40 μl of liquid scintillation cocktail(Microscint-O) was added to each well, and membrane-bound [³⁵S]GTPγS wasmeasured in a 96-well scintillation plate reader (Top-Count,Perkin-Elmer, USA). Non-specific [³⁵S]GTPγS binding is determined in thepresence of cold 10 μM GTP. Each curve was performed at least once usingduplicate sample per data point and at 11 concentrations.

Data Analysis

The concentration-response curves of representative compounds of thepresent invention in the presence of added EC₂₅ of mGluR2 agonistglutamate to determine positive allosteric modulation (PAM), weregenerated using the Prism GraphPad software (Graph Pad Inc, San Diego,USA). The curves were fitted to a four-parameter logistic equation(Y=Bottom+(Top-Bottom)/(1+10̂((LogEC₅₀-X)*Hill Slope) allowingdetermination of EC₅₀ values. The EC₅₀ is the concentration of acompound that causes a half-maximal potentiation of the glutamateresponse. This is calculated by subtracting the maximal responses ofglutamate in presence of a fully saturating concentration of a positiveallosteric modulator from the response of glutamate in absence of apositive allosteric modulator. The concentration producing thehalf-maximal effect is then calculated as EC₅₀.

TABLE 2 Pharmacological data for compounds according to the invention.All compounds were tested in presence of mGluR2 agonist, glutamate at apredetermined EC₂₅ concentration, to determine positive allostericmodulation (GTPγS-PAM). Values shown are averages of duplicate values of11-concentration response curves, from at least one experiment. Alltested compounds showed a pEC₅₀ (−logEC₅₀) value of more than 5.0, from6.09 to 7.40. The error of determination of a pEC₅₀ value for a singleexperiment is estimated to be about 0.3 log-units. GTPgS - hR2 PAM Comp.No. pEC₅₀ 1 n.d. 2 n.d. 3 n.d. 4 6.56 5 6.09 6 6.24 7 7.40 8 n.d. 9 n.d.n.d. = not determined

E. Composition Examples

“Active ingredient” as used throughout these examples relates to a finalcompound of formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms thereof.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol inwater.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

1. A compound having the formula (I)

or a stereochemically isomeric form thereof, wherein R¹ is C₁₋₆alkyl; orC₁₋₃alkyl substituted with C₃₋₇cycloalkyl, phenyl, or phenyl substitutedwith halo, trifluoromethyl or trifluoromethoxy; R² is halo,trifluoromethyl, C₁₋₃alkyl or cyclopropyl; R³ is hydrogen, halo ortrifluoromethyl; R⁴ is hydrogen, C₁₋₃alkyl, C₁₋₃alkyloxy,hydroxyC₁₋₃alkyl or tetrahydropyran-2-yloxyC₁₋₃alkyl; n is 1 or 2; X isa covalent bond, O or NR⁵; R⁵ is hydrogen, C₁₋₃alkyl orhydroxyC₂₋₃alkyl; Y is O or CR⁶(OH); R⁶ is hydrogen or C₁₋₃alkyl; or R⁴and R⁶ form a radical —CH₂—CH₂—; or a pharmaceutically acceptable saltor a solvate thereof.
 2. The compound according to claim 1 wherein R¹ is1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or2-(cyclopropyl)-1-ethyl; R² is halo; R³ is hydrogen, chloro ortrifluoromethyl; R⁴ is hydrogen or hydroxymethyl; N is 2; X is acovalent bond, O or NR⁵; R⁵ is hydrogen; Y is O or CR⁶(OH); R⁶ ishydrogen or methyl; or a pharmaceutically acceptable salt or a solvatethereof.
 3. The compound according to claim 1 wherein R¹ is 1-butyl,3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl; R² ischloro; R³ is hydrogen or chloro; R⁴ is hydrogen or hydroxymethyl; n is2; X is a covalent bond, O or NR⁵; R⁵ is hydrogen; Y is O or CR⁶(OH); R⁶is hydrogen or methyl; or a pharmaceutically acceptable salt or asolvate thereof.
 4. A compound according to claim 1 wherein saidcompound is trifluoro-methanesulfonic acid1-butyl-3-chloro-2-oxo-1,2-dihydropyridin-4-yl ester.
 5. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claim 1 and a pharmaceutically acceptablecarrier or excipient.
 6. A compound according to claim 1 for use as amedicament.
 7. A method for treating or preventing a condition in amammal, the treatment or prevention of which is affected or facilitatedby the neuromodulatory effect of mGluR2 positive allosteric modulators,wherein the method comprises administering to the mammal a compound ofclaim
 1. 8. A method for treating or preventing in a mammal a centralnervous system disorder selected from the group of anxiety disorders,psychotic disorders, personality disorders, substance-related disorders,eating disorders, mood disorders, migraine, epilepsy or convulsivedisorders, childhood disorders, cognitive disorders, neurodegeneration,neurotoxicity and ischemia, wherein the method comprises administeringto the mammal a compound of claim
 1. 9. The method of claim 8, whereinthe central nervous system disorder is an anxiety disorder, selectedfrom the group of agoraphobia, generalized anxiety disorder (GAD),obsessive-compulsive disorder (OCD), panic disorder, posttraumaticstress disorder (PTSD), social phobia and other phobias.
 10. The methodof claim 8, wherein the central nervous system disorder is a psychoticdisorder selected from the group of schizophrenia, delusional disorder,schizoaffective disorder, schizophreniform disorder andsubstance-induced psychotic disorder.
 11. The method of claim 8, whereinthe central nervous system disorder is a personality disorder selectedfrom the group of obsessive-compulsive personality disorder andschizoid, schizotypal disorder.
 12. The method of claim 8, wherein thecentral nervous system disorder is a substance-related disorder selectedfrom the group of alcohol abuse, alcohol dependence, alcohol withdrawal,alcohol withdrawal delirium, alcohol-induced psychotic disorder,amphetamine dependence, amphetamine withdrawal, cocaine dependence,cocaine withdrawal, nicotine dependence, nicotine withdrawal, opioiddependence and opioid withdrawal.
 13. The method of claim 8, wherein thecentral nervous system disorder is an eating disorder selected from thegroup of anorexia nervosa and bulimia nervosa.
 14. The method of claim8, wherein the central nervous system disorder is a mood disorderselected from the group of bipolar disorders (I & II), cyclothymicdisorder, depression, dysthymic disorder, major depressive disorder andsubstance-induced mood disorder.
 15. The method of claim 8, wherein thecentral nervous system disorder is migraine.
 16. The method of claim 8,wherein the central nervous system disorder is epilepsy or a convulsivedisorder selected from the group of generalized nonconvulsive epilepsy,generalized convulsive epilepsy, petit mal status epilepticus, grand malstatus epilepticus, partial epilepsy with or without impairment ofconsciousness, infantile spasms, epilepsy partialis continua, and otherforms of epilepsy.
 17. The method of claim 8, wherein the childhooddisorder is attention-deficit/hyperactivity disorder.
 18. The method ofclaim 8, wherein the central nervous system disorder is a cognitivedisorder selected from the group of delirium, substance-inducedpersisting delirium, dementia, dementia due to HIV disease, dementia dueto Huntington's disease, dementia due to Parkinson's disease, dementiaof the Alzheimer's type, substance-induced persisting dementia and mildcognitive impairment.
 19. The method of claim 8, wherein the centralnervous system disorder is selected from the group of anxiety,schizophrenia, migraine, depression, and epilepsy.
 20. The method ofclaim 7, further comprising administering an orthosteric agonist ofmGluR2 in combination with the compound of claim
 1. 21. (canceled) 22.(canceled)